Development of effective therapies for treatment of acute lung injury (ALI) and adult respiratory distress syndrome remains a challenging task. Relatively low efficiency of existing pharmacological therapies may be due to differences between pre-treatment models used in experimental studies and treatment of ongoing condition in clinical scenarios. It is very possible that pre- and post-treatment models target distinct molecular pathways activated during onset, peak and resolution phases of ALI. Our pioneering studies during the previous cycle characterized barrier-protective properties of oxidized phospholipids (OxPLs). We have described molecular mechanisms of endothelial barrier enhancement and protection during OxPL co-treatment in septic (LPS) and aseptic (Thrombin, IL-6, pathologic mechanical ventilation) models of ALI. We identified key roles of small GTPases Rap1, Rac, Cdc42 and Rap/Rac-Rho crosstalk mechanism in OxPL-dependent control of cytoskeleton, cell-cell junctions and endothelial barrier. Pilot studies for this application reveaed unique protective effects of OxPL post-treatment still achieved after 16 hrs of inflammatory insult. Preliminary data show OxPL-dependent induction of lipoxin, a lipid mediator shown to downregulate existing inflammation and promote resolution. Our pilot studies also suggest involvement of prostanoid family receptor EP4 and cell membrane-associated OxPL-interacting protein GRP78, recently described by our group, in anti- inflammatory effects and restoration of endothelial barrier properties and lung function induced by OxPL post- treatment in the mouse model of ALI caused by Gram-positive pathogens. Aim-1 will test the hypothesis that beneficial effects of OxPL post-treatment in the Staphylococcus aureus model of lung injury involve OxPL- induced lipoxin induction leading to suppression of inflammation and improved ALI recovery. Aim-2 will test the hypothesis that lipoxin pathway is initiated by OxPL-induced activation of GRP78-EP4 signaling complex in the caveolin enriched microdomains (CEM). This proposal will further explore therapeutic potential of OxPL post-treatment, and Aim-3 will test effects of a group of synthetic cleavage-resistant phospholipid compounds generated in our group as prototypes for future treatments. The results of this project will uncover novel, previously unexpected mechanisms accelerating ALI recovery by oxidized phospholipids and may lead to discovery of a new group of pharmacological molecules for the treatment of ALI, ARDS, and other diseases associated with increased vascular leakage and inflammation.